Alcoholic beverages are known human carcinogens that raises the risk of oropharyngeal cancers, liver cancer, breast cancer and others. The reason why these beverages is unknown, but several possibilities exist. We studied a genetic polymorphism in the alcohol dehydrogenase 3, which varies among Caucasians, that results in different inherited capacities to metabolize ethanol to acetaldehyde. Thus, we were seeking to define the risk from alcoholic beverages, and find support for an acetaldehyde hypothesis. We examined this gene in a case control study of breast cancer from Buffalo, New York (in collaboration with Jo Freudenheim and Christine Ambrosone). We found that the same genotype increased the risk of breast cancer in premenopausal Caucasian women. Thus, consistent data from two study populations for two different cancer sites (a positive result was also found for oral cavity cancer) suggests that this gene is important in cancer risk, and that the increased cancer risk is related to acetaldehyde. The etiology of breast cancer includes family and hormonal related factors. However, these only account for a portion of the risk. We have hypothesized that there are susceptible subgroups of women who are harmed by tobacco constituents, based on their ability to metabolize carcinogens, while others might be protected due to the anti-estrogenic effects of tobacco. In collaboration with Christine Ambrosone and Jo Freudenheim, we studied Caucasian women in a population-based case- control study of breast cancer. We found that postmenopausal women who smoked were at a dose-related increased risk if they were slow acetylators for the NAT2 gene, and also at increased risk if they were light smokers and had a variant of the CYP1A1 gene. Premenopausal women were at increased risk if they were smokers and had a variant of the CYP2E1 gene. Taken together, the data implicates tobacco smoke as a breast cancer risk factor in susceptible women, and the study of women based on exposure and genetic polymorphisms provides an additional way to elucidate breast cancer risk factors. Corroborative in vitro cell culture studies and case-series analyses are underway.